Cellular and molecular mechanism of tissue- and species-specific modulation of signaling outcomes

Abstract

To understand the causal relationship between physiological stimuli and outcomes and how it is modulated underlies the investigation of the molecular mechanism of diverse biological processes. However, response to a physiological stimulus does not follow one-to-one correspondence function. Through evolution, the cumulative changes in the heritable characteristics of biological populations, speciation occurs and populations evolve to become distinct species. During embryonic development, diverse tissues are derived from their origin; fertilized egg. Even if the species are different, the response to a stimulus could share high similarity in both species sharing common ancient species. Contrastively, in an organism, tissues derived from distinct structures respond differently to the same biological input, in some instance. It is widely accepted that outcomes of extracellular stimulations are determined by interaction of the stimuli, the receptors, and the effectors. The best known example of such a cascade would be the signaling pathway. While it is increasingly evident that effects of extracellular stimuli, which are physical, chemical, and biological in nature, govern diverse physiological processes, how one specific stimulation which invariably activates the identical downstream effectors could create unique outcomes in a tissue- or species-specific manner, remains largely unknown. In my thesis research, I aimed to understand how the same stimulation could provide unique regulatory inputs in different settings, using two experimental conditions. In the first condition, where I alter the nutrient composition in zebrafish and mice, I found that such a stimulus could elicit distinct changes in gene expression from each species. However, the effects of stimulus appear to converge as GO terminology analyses revealed that distinct genes but with similar function are upregulated in both species. Conversely, where I stimulated two distinct tissues of zebrafish with the identical stimulus, I found outcomes of the stimulus are the opposite in two distinct tissues, suggesting that even within an individual, the outcomes of the stimulus could widely vary. In Part I, I compared the transcriptomic profile of high fat diet zebrafish and mice to examine the biological innate difference about lipid metabolism between zebrafish and mice. Using that data, I identified a set of genes which is selectively upregulated or downregulated in zebrafish. However, my data of GO term analyses and KEGG pathway analyses revealed that similar signaling pathways upregulated in zebrafish and mice as a response to a high fat diet, and this indicates that evolutionary convergence between these two pokilotherm and homeotherm species. In Part II, I examined the response to BMP signaling in the ventral fin fold and the pectoral fins of zebrafish. While the ventral fin fold belongs to unpaired fins and is derived from the paraxial mesoderm, pectoral fins belong to paired fins and diverge from the lateral plate mesoderm. Unpaired fins and paired fins share some similarities in structure and regulatory mechanism, however, they also have distinctive features. I investigated the modulation of outgrowth of the ventral fin fold and pectoral fins in response to BMP signaling using chemical and genetic manipulation-induced BMP signaling inhibition. I found that lack of BMP signaling induces changes of proliferative capacity, propensity of cell division, orientation of cell division and tendency of epithelial cell migration along proximodistal and anteroposterior axes. This suggests that BMP signaling restricts the outgrowth of the ventral fin fold during zebrafish development.